Innate Immune Effectors in Mycobacterial Infection

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2011, Article ID 347594, 8 pages doi:10.1155/2011/347594 Review Article Innate Immune Effectors in Mycobacterial Infection Hiroyuki Saiga,1 Yosuke Shimada,1, 2 and Kiyoshi Takeda1, 2 1 Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan 2 WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Correspondence should be addressed to Kiyoshi Takeda, Received 4 October 2010; Revised 13 December 2010; Accepted 22 December 2010 Academic Editor: Carl Feng Copyright © 2011 Hiroyuki Saiga et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Tuberculosis, which is caused by infection with Mycobacterium tuberculosis (Mtb), remains one of the major bacterial infections worldwide. Host defense against Mtb is mediated by a combination of innate and adaptive immune responses. In the last 15 years, the mechanisms for activation of innate immunity have been elucidated. Toll-like receptors (TLRs) have been revealed to be critical for the recognition of pathogenic microorganisms including mycobacteria. Subsequent studies further revealed that NOD-like receptors and C-type lectin receptors are responsible for the TLR-independent recognition of mycobacteria. Several molecules, such as active vitamin D3 , secretary leukocyte protease inhibitor, and lipocalin 2, all of which are induced by TLR stimulation, have been shown to direct innate immune responses to mycobacteria. In addition, Irgm1-dependent autophagy has recently been demonstrated to eliminate intracellular mycobacteria. Thus, our understanding of the mechanisms for the innate immune response to mycobacteria is developing. 1. Introduction In humans, tuberculosis is one of deadly infectious diseases. Indeed, approximately 2 million tuberculosis patients die every year. The risk of disease is also increased by emergence of acquired immune deficiency syndrome and development of multidrug-resistant mycobacteria [1]. Therefore, it is important to understand the host defense mechanisms against mycobacteria. Inhalation of aerosols containing Mycobacterium tuberculosis (Mtb) causes tuberculosis. After inhalation, Mtb invades alveolar macrophages to enter into the host and establish the infection. The host, in turn, ignites defense responses through sequential activation of immunity, a combination of innate and adaptive immune systems. In the adaptive phase of immune responses, the importance of Th1/IFN-γ-mediated responses in mycobacterial infection has been well established [2]. In contrast, although macrophages are the major target of invasion by Mtb, how the innate arm of immunity mediates host defense against mycobacteria had long remained unknown. However, the mechanisms behind innate immune responses have been revealed in the past 15 years following the identification and characterization of pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) [3]. Furthermore, it has been elucidated that TLR-dependent activation of innate immunity controls the development of adaptive immune responses [4]. The involvement of PRRs other than TLRs in the recognition of mycobacteria has also been revealed. In addition to the induction of adaptive immune responses, the PRR recognition of mycobacteria induces expression of several effector molecules participating in the innate host responses. The role of these innate effector molecules in mycobacterial infection is being elucidated. PRR-independent mechanisms for mycobacterial killing, such as autophagy, have also been revealed. In this paper, we will describe recent advances in our understanding of effectors that mediate innate immune responses against mycobacteria. 2. Toll-Like Receptors in Mycobacterial Infection Innate immune responses after mycobacterial infection are initiated by recognition of mycobacterial components by PRRs, with mycobacterial components activating several 2 TLRs (Figure 1). Genomic DNA from a Mycobacterium bovis strain, bacillus Calmette–Guérin (BCG), have an ability to augment NK cell activity and induce type I IFNs from murine spleen cells and human peripheral blood lymphocytes. The immunostimulatory activity of mycobacterial DNA was ascribed to the presence of palindromic sequences including the 5 -CG-3 motif, now called CpG motif [5], and now known to activate TLR9 [6]. The mycobacterial cell wall consists of several glycolipids. Among these, lipoarabinomannan (LAM) lacking mannose end capping, lipomannan (LM), and phosphatidyl-myo-inositol mannoside (PIM) are recognized by TLR2 [7, 8]. The 19-kDa lipoprotein of Mtb also activates macrophages via TLR2 [9, 10]. TLR4 is also presumed to recognize mycobacterial components. The in vivo importance of the TLR-mediated signal in host defense to Mtb was highlighted in studies using mice lacking MyD88, a critical component of TLR signaling. MyD88-deficient mice are highly susceptible to airborne infection with Mtb [11–13]. In contrast to mice lacking MyD88, mice lacking individual TLRs are not dramatically susceptible to Mtb infection. Susceptibility of TLR2-deficient mice to Mtb infection varies between different studies [14, 15], while TLR4-deficient mice do not show high susceptibility to Mtb infection [16, 17]. A report demonstrates that TLR9-deficient mice are susceptible to Mtb infection and mice lacking both TLR2 and TLR9 are more susceptible [18]. These findings indicate that multiple TLRs might be involved in mycobacterial recognition. However, a recent report using mice lacking TLR2/TLR4/TLR9 indicated that these triple KO mice show a milder phenotype than MyD88deficient mice [12]. Therefore, more intensive examination is required to reveal whether TLRs or molecules other than TLRs activating MyD88 mediate innate immune responses to mycobacterial infection. This study also demonstrated that Th1-like adaptive immune responses are induced even in Mtb-infected MyD88-deficient mice [12]. Therefore, the TLR/MyD88-independent component of innate immunity is involved in the induction of adaptive immune responses during mycobacterial infection. The TLR/MyD88-independent response might be induced by other PRRs described below. 3. Non-TLRs in Mycobacterial Infection Several recent findings have indicated that PRRs other than TLRs evoke innate immune responses [19]. These include RIG-I-like receptors, NOD-like receptors (NLRs), and C-type lectin receptors. Among these PRRs, NOD-like receptors and C-type lectin receptors have been implicated in the innate recognition of mycobacteria (Figure 2). NOD2 is a member of NLRs that recognize muramyl dipeptide (MDP), a core component of bacterial peptidoglycan, in the cytoplasmic (...truncated)